The long-term objective of this project is to understand how cell-cell interactions are down-regulated in invasive carcinomas. The hypothesis to be tested is that a novel mechanism of E-cadherin inactivation occurs in some tumors, thus promoting loss of cell-cell interactions. It is proposed that expression of an inappropriate cadherin (i.e., a mesenchymal cadherin in an epithelial cell) down-regulates the normal endogenous epithelial cadherin(s). Preliminary data have been obtained suggesting that inappropriate expression of N-cadherin by squamous epithelial cells both down-regulates E-cadherin and results in decreased cell-cell adhesion and a more scattered, fibroblast-like morphology. The specific aims are: 1) To determine which domain(s) of N-cadherin are responsible for down-regulating the expression of E-cadherin and for producing a fibroblastic phenotype in oral squamous epithelial cells; 2) To determine whether N-cadherin is unique in its ability to alter the phenotype of squamous epithelial cells by determining if other non-epithelial cell cadherins (e.g., cadherin 4, cadherin 6 or cadherin 11) produce similar results; and 3) To determine the mechanisms that confer a scattered phenotype upon squamous epithelial cells. The change in phenotype may be due to a number of activities including decreased cell-cell adhesion or increased motility. To help sort out these two possibilities, studies will be performed to down-regulate E-cadherin expression without the complications of altering the expression of N-cadherin.